2.1. CLIOQUINOL
Clioquinol has been formulated and administered in various ways, at various doses (Ozawa et al., 1986, Acta Nueropathol (Berl) 69:272-277; Yamanaka et al., 1973, J. Biochem. 73:993-998; Sobue et al., 1971, Neurology 21:168-173; Tamura et al., 1973, Clinica Chimica Acta. 47:13-20; Jack and Riess, 1973, J. Pharm. Sci. 62(12):1929-1932; Baumgartner et al., 1979, Journal of Neurology, Neurosurgery, and Psychiatry 42:1073-1083, Kono, 1975, Japan. J. Med. Sci. Biol. 28:1-21; Sargeaunt and Lumsden, 1976, Transactions of the Royal Society of Tropical medicine and Hygiene 70(1):54-56; Nakae et al., 1973, Lancet 171-173; Mumenthaler et al., 1979, Journal of Neurology, Neurosurgery, and Psychiatry 42:1084-1090; Schmid et al., 1973, Arzneim.-Forsch. (Drug Res.) 23(11):1560-1566; Oakley, 1973, JAMA 225(4):395-397; David et al., 1943, American J. Trop. Med. 24:29-33; Thomas et al., 1984, Journal of the Neurological Sciences 64:277-295; Yoshimura, 1992, Molecular and Chemical Neuropathology 16:59-84; Nakae, 1974, Japan Public Health Journal 15:607-611; Tateishi, 1973, Japan Public Health Journal 15:187-196; Degen et al., 1979, Dermatologica 159:295-301; Goto et al., 1982, J. Toxicological Sciences 7:1-12).
Clioquinol (5-chloro-7-iodo-8 hydroxyquinoline) was previously frequently used for the treatment of various disorders, such as amoebiasis and non-specific infectious diarrhea (Kono, 1975, Japan J. Med. Sci. Biol. 28:1-19, Meade, 1975, Brit. J. Prev. Soc. Med. 29:157-169). However, the use of clioquinol was stopped in Japan when the Japanese Government officially banned the sale in September 1970. The ban was motivated by the presumption that clioquinol caused subacute myelo-optico-neuropathy (SMON). Subsequently, clioquinol was withdrawn from the market in most other countries of the world on the recommendation of the World Health Organization. At present, clioquinol is only used topically due to its antibacterial and anti-fungal activity in skin infections.
SMON develops with an acute or subacute onset preceded by abdominal disorders and is characterized by dysesthesia of the legs, sensory disturbances, a variable degree of motor weakness, and visual loss. Corresponding to these clinical findings, SMON reveals pathologically symmetrical degeneration in peripheral nerves, spinal cord, posterior column, cardiac-spinal tract, and optic nerves.
The occurrence of SMON was confined to Japan even though clioquinol was prescribed world wide and not only in Japan. In the published literature no systematic pathological features resulting from the administration of clioquinol have been described other than the cases of SMON in Japan.
Although, in March 1972, the SMON Research Commission in Japan established a guideline for the treatment of SMON, wherein vitamin B.sub.12 was recommended to be administered as part of a supply of various vitamins (Jap. Med. Sci. Biol. 28 Suppl. (1975)), it was never recognized that the deficiency of vitamin B.sub.12, at least to some extent, might be responsible for SMON. Actually, the effect of vitamin B.sub.12 in the treatment of SMON has been contested by Okuda, K. ("On vitamin B.sub.12 metabolism in SMON patients years after the onset." Report of SMON Research Commission in 1972 (1973) 86), who reported that the vitamin B.sub.12 level in the serum of SMON patients is normal. It was also observed that there may be pathological differences between SMON and B.sub.12 deficiency. (Ricoy et al., 1982, J. Neurol. Sci. 53:241-251.) Hence, it was supposed that the administration of vitamin B.sub.12 would not produce any improvement in the symptoms and signs of SMON.
After the withdrawal of clioquinol from the market there was a dramatic disappearance of new cases of SMON. At present, clioquinol is used topically due to its antibacterial and anti-fungal activity in skin infections.
Clioquinol has recently been shown to be effective in the treatment of Heliocobacter pylori (see International Publication No. WO 95/31199, dated Nov. 23, 1995) and neurotoxic injury (see International Publication No. WO 97/09976, dated Mar. 20, 1997 of Washington University).
The chelating ability of clioquinol is known for Fe, Co, Ni and Zn (Kidani et al., 1974, Jap. Analyst 23:1375-1378). Using mass spectrophotometry the coordination number for clioquinol for Co(II), Ni(II), Cu(II) and Zn(II) is 2, whereas the coordination number for Fe(III) is 3. Reportedly, injected preparations of clioquinol have crossed the blood-brain-barrier, leaving concentrations thereof in the brain on the order of 20 .mu.l/ml when administered at dosages of 10-20 mg/kg (Tateishi et al., 1973, Psychiat. Neurol. Jap. 75:187-196 and Tamura, 1975, Jap. J. Med. Sci. Biol. Suppl 28:69-77). The concentration of clioquinol was also found to be high in such areas of the brain as the hippocampus.
Using microautoradiographic techniques, clioquinol has been shown in monkeys to form zinc chelates in the hippocampus. The Zn(II) chelates were mainly found in the terminal axodendritic boutons of the mossy fibres. Unconjugated clioquinol has an extremely rapid penetration into the nervous system when injected intravenously, with the ability to cross the blood-brain-barrier (Shiraki, 1979, In: Intoxications of the Nervous System. Part II. Handbook of Clinical Neurology, Vinken et al. eds., North Holland Publishing Co., New York, pp. 115-139).
Renewed interest has been evinced in clioquinol recently as it has been shown to be effective in the treatment of Heliocobacter pylori (see International Publication No. WO 95/31199, dated Nov. 23, 1995) and neurotoxic injury (see International Publication No. WO 97/09976, dated Mar. 20, 1997 of Washington University). In another filed, but not yet published, patent application, of the present applicant, clioquinol is disclosed to have activity in the treatment of Alzheimer's disease (PCT/IB97/00983, filed Aug. 8, 1997). Further, it is supposed that clioquinol has activity in the treatment of Parkinson's Disease. The aforementioned applications and publications are incorporated herein by reference in their entireties.